SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing

Muhammad Tariq, John W. Belmont, Seema Lalani, Teresa Smolarek, Stephanie Ware

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Heterotaxy-spectrum cardiovascular disorders are challenging for traditional genetic analyses because of clinical and genetic heterogeneity, variable expressivity, and non-penetrance. In this study, high-resolution SNP genotyping and exon-targeted array comparative genomic hybridization platforms were coupled to whole-exome sequencing to identify a novel disease candidate gene. Results: SNP genotyping identified absence-of-heterozygosity regions in the heterotaxy proband on chromosomes 1, 4, 7, 13, 15, 18, consistent with parental consanguinity. Subsequently, whole-exome sequencing of the proband identified 26065 coding variants, including 18 non-synonymous homozygous changes not present in dbSNP132 or 1000 Genomes. Of these 18, only 4 - one each in CXCL2, SHROOM3, CTSO, RXFP1 - were mapped to the absence-of-heterozygosity regions, each of which was flanked by more than 50 homozygous SNPs confirming recessive segregation of mutant alleles. Sanger sequencing confirmed the SHROOM3 homozygous missense mutation and it was predicted as pathogenic by four bioinformatic tools. SHROOM3 has been identified as a central regulator of morphogenetic cell shape changes necessary for organogenesis and can physically bind ROCK2, a rho kinase protein required for left-right patterning. Screening 96 sporadic heterotaxy patients identified 4 additional patients with rare variants in SHROOM3. Conclusions: Using whole exome sequencing, we identify a recessive missense mutation in SHROOM3 associated with heterotaxy syndrome and identify rare variants in subsequent screening of a heterotaxy cohort, suggesting SHROOM3 as a novel target for the control of left-right patterning. This study reveals the value of SNP genotyping coupled with high-throughput sequencing for identification of high yield candidates for rare disorders with genetic and phenotypic heterogeneity.

Original languageEnglish
JournalGenome Biology
DOIs
StateAccepted/In press - Sep 21 2011
Externally publishedYes

Fingerprint

Exome
genotyping
Single Nucleotide Polymorphism
missense mutation
heterozygosity
Genetic Heterogeneity
mutation
Missense Mutation
comparative genomic hybridization
screening
bioinformatics
Heterotaxy Syndrome
organogenesis
Consanguinity
protein kinases
rho-Associated Kinases
Chromosomes, Human, Pair 4
cardiovascular diseases
exons
Comparative Genomic Hybridization

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing. / Tariq, Muhammad; Belmont, John W.; Lalani, Seema; Smolarek, Teresa; Ware, Stephanie.

In: Genome Biology, 21.09.2011.

Research output: Contribution to journalArticle

Tariq, Muhammad ; Belmont, John W. ; Lalani, Seema ; Smolarek, Teresa ; Ware, Stephanie. / SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing. In: Genome Biology. 2011.
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AB - Background: Heterotaxy-spectrum cardiovascular disorders are challenging for traditional genetic analyses because of clinical and genetic heterogeneity, variable expressivity, and non-penetrance. In this study, high-resolution SNP genotyping and exon-targeted array comparative genomic hybridization platforms were coupled to whole-exome sequencing to identify a novel disease candidate gene. Results: SNP genotyping identified absence-of-heterozygosity regions in the heterotaxy proband on chromosomes 1, 4, 7, 13, 15, 18, consistent with parental consanguinity. Subsequently, whole-exome sequencing of the proband identified 26065 coding variants, including 18 non-synonymous homozygous changes not present in dbSNP132 or 1000 Genomes. Of these 18, only 4 - one each in CXCL2, SHROOM3, CTSO, RXFP1 - were mapped to the absence-of-heterozygosity regions, each of which was flanked by more than 50 homozygous SNPs confirming recessive segregation of mutant alleles. Sanger sequencing confirmed the SHROOM3 homozygous missense mutation and it was predicted as pathogenic by four bioinformatic tools. SHROOM3 has been identified as a central regulator of morphogenetic cell shape changes necessary for organogenesis and can physically bind ROCK2, a rho kinase protein required for left-right patterning. Screening 96 sporadic heterotaxy patients identified 4 additional patients with rare variants in SHROOM3. Conclusions: Using whole exome sequencing, we identify a recessive missense mutation in SHROOM3 associated with heterotaxy syndrome and identify rare variants in subsequent screening of a heterotaxy cohort, suggesting SHROOM3 as a novel target for the control of left-right patterning. This study reveals the value of SNP genotyping coupled with high-throughput sequencing for identification of high yield candidates for rare disorders with genetic and phenotypic heterogeneity.

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